Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives

ABSTRACT

Disclosed are the compounds of formula Iwherein R is methyl or ethyl; R1 is chloro or fluoro; R2 is hydrogen or fluoro; R3 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R4 is hydrogen or fluoro; and R5 is chloro, fluoro, trifluoromethyl or methyl; and pharmaceutically acceptable salts thereof, as selective COX-2 cyclooxygenase inhibitors; and pharmaceutically acceptable prodrug esters thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No.60/069,837 filed Aug. 28, 1997 and of U.S. provisional application No.60/057,803 filed Aug. 28, 1997.

BACKGROUND AND SUMMARY OF THE INVENTION

The invention relates to 5-alkyl-2-arylaminophenylacetic acids andderivatives thereof as defined herein which are particularly potent andselective cyclooxygenase-2(COX-2) inhibitors, methods for preparationthereof, pharmaceutical compositions comprising said compounds, methodsof selectively inhibiting COX-2 activity and of treating conditions inmammals which are responsive to COX-2 inhibition using said compounds orpharmaceutical compositions comprising said compounds of the invention.

Various substituted 2-arylaminophenylacetic acids and derivativesthereof have been disclosed e.g. in J. Med. Chem. 33, 2358 (1990), U.S.Pat. Nos. 3,558,690, 3,652,762, 4,173,577 and 4,548,952, and in PCTapplications WO 94/104484, WO 97/09977, WO 96/00716 and DE 13,445,011 asanalgesic agents, non-steroidal antiinflammatory agents andcyclooxygenase inhibitors. As to 5-alkyl-2-arylaminophenylacetic acids,the only example known to be described in the literature is5-methyl-2-(2,6-dimethylanilino)-phenylacetic acid and its sodium salt(U.S. Pat. No. 3,558,690) for which no biological data has beenreported.

2-(2,6-Dichlorophenylamino) phenylacetoxyacetic acid (aceclofenac) andsalts thereof have been disclosed e.g. in U.S. Pat. No. 4,548,952, andin PCT application WO 96/00716 as non-steroidal antiinflammatory andanalgesic agents. The pharmacological properties of aceclofenac areapparently the result of in vivo conversion to diclofenac and/orderivatives thereof.

Non-steroidal antiinflammatory agents block prostaglandin synthesis byinhibition of the enzyme cyclooxygenase. Cyclooxygenase is now known tocomprise a constitutive isoform (cyclooxygenase-1, COX-1) and aninducible isoform (cyclooxygenase-2, COX-2). COX-1 appears responsiblefor protective beneficial features of prostaglandins, e.g. for thegastrointestinal tract, kidney, etc., while the inducible isoform COX-2appears responsible for pathological conditions associated withprostaglandins, such as inflammatory conditions. A limitation to the useof conventional nonsteroidal antiinflammatory drugs (NSAIDS), includingaceclofenac and diclofenac sodium which is the sodium salt of2,6-dichloroanilinophenylacetic acid, is gastrointestinal toxicity nowattributed to the inhibition of the COX-1 isoform of cyclooxygenase.Selective inhibition of inducible COX-2 in vivo has been reported to beantiinflammatory and non-ulcerogenic (Proc. Natl. Acad. Sci. (U.S.A.)1994; 91:3228-3232).

The present invention provides novel 5-alkyl substituted2-arylaminophenylacetic acids and derivatives which surprisingly inhibitCOX-2 without significantly inhibiting COX-1. The invention thusprovides novel nonsteroidal antiinflammatory agents which aresurprisingly free of undesirable side effects usually associated withthe classical nonsteroidal antiinflammatory agents, such asgastrointestinal and renal side effects. The compounds of the presentinvention are thus particularly useful or may be metabolically convertedto compounds which are particularly useful as COX-2 selectivecyclooxygenase inhibitors. They are thus particularly useful for thetreatment of cyclooxygenase-2 dependent disorders in mammals, includinginflammation, pyresis, pain, osteoarthritis, rheumatoid arthritis,migraine headache, cancer such as digestive tract (e.g. colon) cancerand melanoma, neurodegenerative diseases (such as multiple sclerosis),Alzheimer's disease, osteoporosis, asthma, lupus and psoriasis whilesubstantially eliminating undesirable gastrointestinal ulcerationassociated with conventional cyclooxygenase inhibitors. The compounds ofthe invention are also UV absorbers, in particular UV-B absorbers, andare useful for blocking or absorbing UV radiation, for instance for thetreatment and prevention of sunburn, e.g. in suntan products.

Ocular applications of the compounds of the invention include thetreatment of ocular inflammation, of ocular pain including painassociated with ocular surgery such as PRK or cataract surgery, ofocular allergy, of photophobia of various etiology, of elevatedintraocular pressure (in glaucoma) by inhibiting the production oftrabecular meshwork inducible glucocorticoid response (TIGR) protein andof dry eye disease.

The compounds of the present invention are useful for the treatment ofneoplasia particularly neoplasia that produce prostaglandins or expresscyclooxygenase, including both benign and cancerous tumors, growths andpolyps, in particular epithelium cell-derived neoplasia. Compounds ofthe present invention are in particular useful for the treatment ofliver, bladder, pancreatic, ovarian, prostate, cervical, lung and breastcancer and, especially gastrointestinal cancer, for example cancer ofthe colon, and skin cancer, for example squamous cell or basal cellcancers and melanoma, as indicated above.

The term “treatment” as used herein is to be understood as includingboth therapeutic and prophylactic modes of therapy, e.g. in relation tothe treatment of neoplasia, therapy to prevent the onset of clinicallyor preclinically evident neoplasia, or for the prevention of initiationof malignant cells or to arrest or reverse the progression ofpremalignant to malignant cells, as well as the prevention or inhibitionof neoplasia growth or metastasis. In this context, the presentinvention is, in particular, to be understood as embracing the use ofcompounds of the present invention to inhibit or prevent development ofskin cancer, e.g. squamous or basal cell carcinoma consequential to UVlight exposure, e.g. resulting from chronic exposure to the sun.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds of formula I

wherein R is methyl or ethyl;

R₁ is chloro or fluoro;

R₂ is hydrogen or fluoro;

R₃ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy orhydroxy;

R₄ is hydrogen or fluoro; and

R₅ is chloro, fluoro, trifluoromethyl or methyl;

pharmaceutically acceptable salts thereof; and

pharmaceutically acceptable prodrug esters thereof.

A particular embodiment of the invention relates to the compounds offormula I wherein R is methyl or ethyl; R₁ is chloro or fluoro; R₂ ishydrogen; R₃ is hydrogen, fluoro, chloro, methyl or hydroxy; R₄ ishydrogen; and R₅ is chloro, fluoro or methyl; pharmaceuticallyacceptable salts thereof, and pharmaceutically acceptable prodrug estersthereof.

A preferred embodiment relates to the compounds of formula I wherein Ris methyl or ethyl; R₁ is fluoro; R₂ is hydrogen; R₃ is hydrogen, fluoroor hydroxy; R₄ is hydrogen; and R₅ is chloro; pharmaceuticallyacceptable salts thereof; and pharmaceutically acceptable prodrug estersthereof.

Another preferred embodiment of the invention relates to compound offormula I wherein R is ethyl or methyl; R₁ is fluoro; R₂ is hydrogen orfluoro; R₃ is hydrogen, fluoro, ethoxy or hydroxy; R₄ is hydrogen orfluoro; and R₅ is chloro, fluoro or methyl; pharmaceutically acceptablesalts thereof; and pharmaceutically acceptable prodrug esters thereof.

Further preferred are said compounds wherein R is methyl or ethyl; R₁ isfluoro; R₂-R₄ are hydrogen or fluoro; and R₅ is chloro or fluoro;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable prodrug esters thereof.

A further embodiment of the invention relates to the compounds offormula I wherein R is methyl or ethyl; R₁ is fluoro; R₂ is fluoro; R₃is hydrogen, ethoxy or hydroxy; R₄ is fluoro; and R₅ is fluoro;pharmaceutically acceptable salts thereof; and pharmaceuticallyacceptable prodrug esters thereof.

Another preferred embodiment of the invention relates to the compoundsof formula I wherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ ishydrogen or fluoro; R₄is hydrogen; and R₅ is chloro; pharmaceuticallyacceptable salts thereof; and pharmaceutically acceptable prodrug estersthereof. Particular embodiments of the invention relate to compounds offormula I

(a) wherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is hydrogen;R₄ is hydrogen; and R₅ is chloro; pharmaceutically acceptable saltsthereof; and pharmaceutically acceptable prodrug esters thereof,

(b) wherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is fluoro; R₄is hydrogen; and R₅ is chloro; pharmaceutically acceptable saltsthereof; and pharmaceutically acceptable prodrug esters thereof;

(c) wherein R is ethyl; R₁ is fluoro; R₂ is fluoro; R₃ is hydrogen; R₄is fluoro; and R₅ is fluoro; pharmaceutically acceptable salts thereof;and pharmaceutically acceptable prodrug esters thereof; and

(d) wherein R is ethyl; R₁ is chloro; R₂ is hydrogen; R₃ is chloro; R₄is hydrogen; and R₅ is methyl; pharmaceutically acceptable saltsthereof; and pharmaceutically acceptable prodrug esters thereof.

The general definitions used herein have the following meaning withinthe scope of the present invention.

Pharmaceutically acceptable prodrug esters are ester derivatives whichare convertible by solvolysis or under physiological conditions to thefree carboxylic acids of formula I. Such esters are e.g. lower alkylesters (such as the methyl or ethyl ester), carboxy-lower alkyl esterssuch as the carboxymethyl ester, nitrooxy-lower alkyl esters (such asthe 4-nitrooxybutyl ester), and the like. Preferred are the 5-alkylsubstituted 2-arylaminophenylacetoxyacetic acids of formula la

wherein R and R₁-R₅ have meaning as defined hereinabove for compounds offormula I; and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts represent metal salts, such asalkaline metal salts, e.g. sodium, potassium, magnesium or calciumsalts, as well as ammonium salts, which are formed e.g. with ammonia andmono- or di-alkylamines, such as diethylammonium salts, and with aminoacids, such as arginine and histidine salts.

A lower alkyl group contains up to 7 carbon atoms, preferably 1 to 4carbon atoms and represents for example methyl, ethyl, propyl or butyl,and may be straight chain or branched.

The compounds of the invention are useful as selective cyclooxygenase-2inhibitors or as prodrugs thereof. The selective cyclooxygenase-2(COX-2) inhibitors and prodrugs thereof of the invention areparticularly useful for the treatment of e.g. inflammation, pyresis,pain, osteoarthritis, rheumatoid arthritis and other conditionsresponsive to the inhibition of cyclooxygenase-2 and are typicallysubstantially free of undesirable gastrointestinal side effectsassociated with conventional non-steroidal antiinflammatory agents.

The above-cited properties are demonstrable in vitro and in vivo testsusing advantageously mammals, e.g. rats, mice, dogs, monkeys andisolated cells or enzyme preparations thereof. Said compounds can beapplied in vitro in the form of solutions, e.g. aqueous solutions, andin vivo advantageously orally, topically or parenterally, e.g.intravenously. The dosage in vitro may range from about 10⁻⁵ to 10⁻⁹molar concentrations. The dosage in vivo may range, depending on theroute of administration, between about 1 and 100 mg/kg.

Cyclooxygenase inhibition is determined in vitro using cellular assaysfor inhibition of both cyclooxygenase-1 and cyclooxygenase-2.

The cellular assays for testing cyclooxygenase inhibitors are based onthe fact that the cyclooxygenase enzyme (prostaglandin H synthase)catalyzes the rate limiting step in prostaglandin synthesis fromarachidonic acid. Two enzymes mediate the reaction: COX-1 is aconstitutive form of the enzyme whereas COX-2 is induced in response tovarious growth factors and cytokines. Cell lines have been establishedwhich express one form of the enzyme: a human skin fibroblast line whichcan be induced with IL-1 to synthesize COX-2, and the kidney epithelialcell line 293 which has been stably transfected to constitutivelyexpress COX-1. Both isoforms metabolize arachidonic acid into the stablemetabolite prostaglandin E₂. Arachidonic acid can be added exogenouslyto increase output to easily measurable levels. The levels ofprostaglandin E₂ in the extracellular medium are assayed byradioimmunoassay as a measure of enzyme activity. The relativeactivities of each isoform are compared to assess compound selectivity.

In vitro cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)inhibition is determined in the cell-based assays in order to assess thein vitro activity and selectivity for COX-2 inhibition, using aprostaglandin E₂ radioimmunoassay. The cells utilized are primary humanfibroblasts induced with interleukin-1 to produce COX-2, and the humankidney epithelial cell line 293 stably transfected to produce COX-1constitutively. Cells are plated out into well plates in which the assayis performed. Fibroblasts are stimulated to synthesize COX-2 bytreatment overnight with IL-1; the 293 cells require no induction. Bothcell lines are pre-treated with compound dilutions for 15 minutes at 37°C., then 40 μM arachidonic acid is added as exogenous substrate for theproduction of PGE₂, which is measured in supernatant byradioimmunoassay. For IC₅₀ determinations, compounds are tested at 5concentrations in quadruplicate (highest concentration 30 μM); the meaninhibition of PGE₂ (compared to cells not treated with compound) foreach concentration is calculated, a plot made of mean % inhibition vs.log compound concentration for all experiments, and the overall IC₅₀value calculated using a 4-parameter logistic fit.

IC₅₀ values for compounds of formula I in the COX-2 inhibition assay areas low as about 0.005 μM whereas IC₅₀ values in the COX-1 inhibitionassay are greater than 30 μM.

Illustrative of the invention, the compounds of examples 1(d), 1(g) and3(a) have an IC₅₀ of about 0.13, 0.25, 0.007 μM, respectively, for COX-2inhibition with no significant COX-1 inhibition at 30 μM.

The inhibition of prostaglandin-E₂ production produced by COX-2 can bedetermined in vivo in the lipopolysaccharide (LPS)-challengedsubcutaneous air pouch model in the rat (see “Advances in InflammationResearch”, Raven Press, 1986 and J. Med. Chem. 39, 1846 (1996)).

Female Lewis rats are anesthetized and then dorsal air pouches areprepared by subcutaneous injection of 10 ml of air through a sterile0.45 micron syringe-adapted filter. Twenty-four hours after preparation,the air pouches are injected with LPS (8 μg/pouch) suspended in sterilephosphate buffered saline. Compounds for evaluation are suspended infortified cornstarch and administered by gavage one hour prior to LPSchallenge. The pouch contents are harvested three hours after LPSchallenge and PGE₂ levels present in the pouch fluids are measured byenzyme immunoassay. ED₅₀ values for inhibition of PGE₂ formation arecalculated by least squares linear regression. Illustrative of theinvention, the compounds of examples 1(d), 1(g), 3(a) and 6(a) have anED₅₀ in the range of about 0.2 mg/kg p.o. to about 0.6 mg/kg p.o.

The in vivo inhibition of thromboxane B₂ (TXB₂) produced by COX-1 can bemeasured ex vivo in the serum of rats after oral administration ofcompound.

Briefly, rats are fasted overnight, administered compound in fortifiedcornstarch vehicle by gavage, and sacrificed by carbon dioxideinhalation 30 minutes to eight hours later. Blood is collected bycardiac puncture into tubes without anti-coagulant, allowed to clot andserum is separated by centrifugation. Serum is stored frozen for lateranalysis of thromboxane B₂ by radioimmunoassay. Each experiment containsthe following groups (5-6 rats per group): vehicle control and testcompounds, either at different doses or different time points.Thromboxane B₂ data is expressed as a percentage of the levels measuredin the vehicle control group.

Illustrative of the invention, the compounds of examples 1(d), 1(g),3(a), and 6(a) cause less than a 50% inhibition of serum thromboxane B₂production at an oral dose which is 50-150 times the ED₅₀ value for invivo COX-2 inhibition.

Antiinflammatory activity is determined using the carrageenan inducedrat paw edema assay.

Sprague Dawley rats (200-225 g) are fasted overnight, then orally dosedwith the compound suspended in a fortified cornstarch solution. Afterone hour, a 0.1 ml volume of 1% carrageenan in saline is injected intothe subplantar region of the left hind paw which causes an inflammatoryresponse. At 3 hours post carrageenan, the rats are euthanatized andboth hind paws are cut off at the paw hair line and weighed on anelectronic balance. The amount of edema in the inflamed paw isdetermined by subtracting the weight of the non-inflamed paw (right)from the weight of the inflamed paw (left). The percent inhibition bythe compound is determined for each animal as the percent paw weightgained as compared to the control average. ED₃₀ values are determinedfor each dose-response using the curve fitting formula,

100/1+(Drug Concentration/ED₃₀)^(slope)

Mean ED₃₀ values are calculated as the average of ED₃₀ values determinedfrom independent dose response assays.

Illustrative of the invention, the compounds of examples 1(d), 1(g),3(a) and 6(a) inhibit carrageenan-induced edema with an ED₃₀ in therange of about 0.14 mg/kg p.o. to about 1.65 mg/kg p.o.

The gastric tolerability assay is used to assess gross ulceration in therat, measured four hours after oral administration of the test compound.The test is carried out as follows: Rats are fasted overnight,administered compound in fortified cornstarch vehicle by gavage, andsacrificed by carbon dioxide inhalation four hours later. The stomachsare removed and gross gastric lesions counted and measured to give thetotal lesion length per rat. Each experiment contains the followinggroups (5-6 rats per group): vehicle control, test compounds, anddiclofenac as a reference compound.

Data are calculated as the mean number of ulcers in a group, the meanlength of ulcers (mm) in the group and as the ulcer index (UI).

UI=mean length of ulcers in a group×ulcer incidence

where ulcer incidence is the fraction of animals in the group withlesions (100% incidence is 1).

Illustrative of the invention, the compounds of examples 1(d), 1(g),3(a) and 6(a) are essentially free of any gastric ulcerogenic effect at100 mg/kg p.o.

Intestinal tolerability can be determined by measuring the effect onintestinal permeability. Lack of increase in permeability is indicativeof intestinal tolerability.

The method used is a modification of a procedure by Davies, et al.,Pharm. Res. 1994; 11:1652-1656 and is based on the fact that excretionof orally administered ⁵¹Cr-EDTA, a marker of small intestinalpermeability, is increased by NSAIDs. Groups of rats (≧12/group) areadministered a single, oral dose of test compound or vehicle by gastricintubation. Immediately following compound dose, each rat isadministered ⁵¹Cr-EDTA (5 μCi/rat) by gastric intubation. The rats areplaced in individual metabolic cages and given food and water adlibitum. Urine is collected over a 24 hour period. Twenty-four hoursafter administration of ⁵¹Cr-EDTA the rats are sacrificed. To quantifycompound effect on intestinal permeability, the excreted ⁵¹Cr-EDTAmeasured in the urine of compound treated rats is compared to theexcreted ⁵¹Cr-EDTA measured in the urine of vehicle treated rats.Relative permeability is determined by calculating the activity presentin each urine sample as a percent of the administered dose aftercorrecting for background radiation.

Illustrative of the invention, the compounds of examples 1(d), 1(g),3(a) and 6(a) demonstrate no effect or only a minimal effect onintestinal permeability at a dose of 30 mg/kg p.o.

The analgesic activity of the compounds of the invention is determinedusing the well-known Randall-Selitto assay.

The Randall-Selitto paw pressure assay measures antinociception(analgesic activity) in inflamed tissue by comparing the pressurethreshold in the inflamed paw of the rat after oral administration oftest drug with that in the inflamed paw of rats administered corn starchvehicle orally.

Groups of 10 male Wistar rats weighing 40-50 gms are fasted overnightprior to testing. Hyperalgesia is induced by the injection of 0.1 ml ofa 20% suspension of Brewer's yeast with a 26 gauge needle into thesubplantar region of the right hindpaw. The left paw is not injected andis used as the control paw for determination of hyperalgesia. Vehicle(Fortified corn starch suspension 3%) at 10 ml/kg, reference compound(diclofenac is run in every experiment at the same dose as testcompounds) and test compounds at different doses suspended in vehicle at1 ml/kg are administered orally 2 hours after the yeast injection. Thethreshold for paw withdrawal is quantified with a Basile Analgesy-meter1 hour after oral administration of test compounds. The nociceptivethreshold is defined as the force in grams at which the rat withdrawsits foot or vocalizes. Either vocalization or foot withdrawal isrecorded as a response.

The data are analyzed by comparing the mean pain threshold of the cornstarch vehicle-treated group for the inflamed and non-inflamed paws tothat of individual drug-treated rats. Individual rats in thedrug-treated groups and positive control (diclofenac) group are calledreactors if the individual pain threshold in each paw exceeds thecontrol group mean threshold by two standard deviations of that mean.The mean pain thresholds of the inflamed paw in the control group arecompared to the individual pain thresholds of the inflamed paw in thetest drug group. The non-inflamed control mean pressure threshold iscompared to the non-inflamed individual pressure thresholds in the testgroups. Results are expressed as number of reactors in each test group(n =10) for inflamed and non-inflamed paws. Percentages are calculatedby dividing number of reactors by total number of rats used for acompound.

Illustrative of the invention, the compounds of examples 1(d), 1(g),3(a) and 6(a) all increase the pain threshold in the inflamed paw at 10mg/kg administered orally. These compounds selectively elevate the painthreshold in the inflamed paw with no threshold elevation in thenon-inflamed paw indicating a peripheral mechanism.

The antiarthritic effect of the compounds of the invention can bedetermined in the well-known chronic adjuvant arthritis test in the rat.

Ocular effects can be demonstrated in well-known ophthalmic assaymethods. Similarly antitumor activity can be demonstrated in well-knownantitumor animal tests.

The compounds of formula I can be prepared e.g.

(a) by coupling a compound of formula II or IIa

 wherein R has meaning as defined above; R_(a) is lower alkyl,preferably isopropyl; and R₆ and R₇ represent lower alkyl; or R₆ and R₇together with the nitrogen atom represent piperidino, pyrrolidino ormorpholino;

with a compound of formula III

 wherein R₁, R₂, R₃, R₄ and R₅ have meaning as defined above in thepresence of copper and cuprous iodide to obtain a compound of formula IVor IVa

 and hydrolyzing the resulting compound of formula IV or IVa to acompound of formula I; or

(b) for compounds in which R represents ethyl, by condensing a compoundof formula V

 wherein R₁-R₇ have meaning as defined herein, with a reactivefunctional derivative of acetic acid, such as acetyl chloride, in aFriedel-Crafts acylation to reaction to obtain a compound of the formulaVI

wherein R₁-R₇ have meaning as defined herein which is in turnhydrogenolyzed and then hydrolyzed to obtain a compound of formula Iwherein R represents ethyl; or

(c) by hydrolyzing a lactam of formula VII

 wherein R and R₁-R₅ have meaning as defined herein, with a strong base;and

in above processes, if desired, temporarily protecting any interferingreactive groups and then isolating the resulting compound of theinvention; and, if desired, converting any resulting compound intoanother compound of the invention; and/or if desired converting a freecarboxylic acid of the invention into a pharmaceutically acceptableester derivative thereof; and/or if desired, converting a resulting freeacid into a salt or a resulting salt into the free acid or into anothersalt.

In starting compounds and intermediates, which are converted to thecompounds of the invention in a manner described herein, functionalgroups present such as amino, hydroxy and carboxyl groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected hydroxy, amino and carboxylgroups are those that can be converted under mild conditions into freeamino, hydroxy and carboxyl groups without other undesirable sidereactions taking place. For example, hydroxy protecting groups arepreferably benzyl or substituted benzyl groups, or acyl groups such aspivaloyl.

The preparation of compounds of formula IV according to process (a) iscarried out under conditions of a modified Ullmann condensation for thepreparation of diarylamines, e.g. in the presence of copper powder andcopper (I) iodide and potassium carbonate, in an inert high boilingsolvent such as nitrobenzene, toluene, xylene or N-methylpyrrolidone, atelevated temperature, e.g. in the range of 100°-200° C., preferably atreflux temperature, according to general methodology described by F.Nohara, Chem. Abstr. 94, 15402x (1951) and Moser et al., J. Med. Chem.33, 2358 (1990).

Intermediates of Formula IV wherein R₁, or R₅ is methyl or ethyl can beprepared from intermediates of formula IV, wherein R₁, or R₅ is bromo byreaction with tetramethyltin or tetraethyltin under conditions of a Heckreaction, that is in the presence of a palladium salt (such as Pd(OAc)₂or PdCl₂), a triarylphosphine (such as tri (o-tolyl)phosphine) and abase (such as triethylamine, sodium acetate) in a polar solvent such asdimethylformamide.

Hydrolysis of the resulting ortho-anilinophenylacetamides of formula IVis carried out in aqueous alkali hydroxide, e.g. in 6N NaOH in thepresence of an alcohol (e.g. ethanol, propanol, butanol) at elevatedtemperature, such as reflux temperature of the reaction mixture.

The hydrolysis of esters of formula IVa is carried out according tomethods known in the art, e.g. under basic conditions as described abovefor the compounds of formula IV or alternatively under acidicconditions, e.g. using methanesulfonic acid.

The starting materials of formula 11 or Ha are generally known or can beprepared using methodology known in the art, e.g. as described by F.Nohara in Japanese patent application No. 78/96,434 (1978).

For example, 5-methyl or 5-ethylanthranilic acid is converted to theortho-diazonium derivatives followed by treatment with an alkali metaliodide in acid (e.g. sulfonic acid) to obtain 5-alkyl-2-iodobenzoicacid. Reduction to the corresponding benzyl alcohol (e.g. withdiborane), conversion of the alcohol first to the bromide and then tothe nitrile, hydrolysis of the nitrile to the acetic acid and conversionto the N,N dialkylamide according to methodology known in the art yieldsa starting material of formula II.

Alternatively, the starting materials of formula II wherein R is ethylcan be prepared by Friedel-Crafts acetylation of oxindole with e.g.acetyl chloride in the presence of aluminum chloride, reduction of theresulting ketone by e.g. catalytic hydrogenolysis, followed byhydrolytic cleavage of the resulting 5-ethyloxindole to5-ethyl-2-aminophenylacetic acid. Diazotization in the presence of e.g.potassium iodide yields 5-ethyl-2-iodo-phenylacetic acid which isconverted to an amide of formula II. Esters of formula Ila are preparedfrom the corresponding acids according to esterification methods knownin the art.

The anilines of formula III are either known in the art or are preparedaccording to methods well-known in the art or as illustrated herein.

The preparation of 5-ethyl substituted compounds according to process(b) is carried out under conditions of Friedel-Crafts acylation e.g. inthe presence of aluminum chloride in an inert solvent such as1,2-dichloroethane, followed by hydrogenolysis, e.g. using palladium oncharcoal catalyst, preferably in acetic acid as solvent, at roomtemperature and about 3 atmospheres pressure.

The starting materials of formula V are prepared generally as describedunder process (a) but starting with an amide of formula II in which Rrepresents hydrogen, e.g. as described in J. Med. Chem. 33, 2358 (1990).

The preparation of the compounds of the invention according to process(c) can be carried out under conditions known in the art for thehydrolytic cleavage of lactams, preferably with a strong aqueous base,such as aqueous sodium hydroxide, optionally in the presence of anorganic water miscible solvent such as methanol at elevated temperaturein the range of about 50-100° C., as generally described in U.S. Pat.No. 3,558,690.

The oxindole starting materials are prepared by N-acylation of adiarylamine of the formula VII

wherein R and R₁-R₅ have meaning as defined above with a haloacetylchloride, preferably chloroacetyl chloride, advantageously at elevatedtemperature, e.g. near 100° C., to obtain a compound of the formula IX

wherein R and R₁-R₅ have meaning as defined hereinabove. Cyclization ofa compound of formula IX is carried out under conditions ofFriedel-Crafts alkylation in an inert solvent, such as dichlorobenzene,in the presence of Friedel-Crafts catalysts, e.g. aluminum chloride andethylaluminum dichloride, at elevated temperature, e.g. at 120-175° C.

The diarylamines of formula VIII can be prepared by an Ullmanncondensation and other methods known in the art, e.g. a Buchwaldcoupling reaction.

For example, the diarylamines of formula VIII wherein R₁, R₂, R₄ and R₅are fluoro and R₃ is hydrogen can be prepared by reacting thecorresponding aniline (4-ethyl- or 4-methyl-aniline) withpentafluorobenzene in the presence of a strong base such as lithiumamide or n-butyllithium, as generally described in J. of FluorineChemistry 5, 323 (1975).

Esters of the carboxylic acids of formula I are prepared by condensationof the carboxylic acid, in the form of a salt or in the presence of abase, with a halide (bromide or chloride) corresponding to theesterifying alcohol (such as benzyl chloroacetate) according tomethodology well known in the art, e.g. in a polar solvent such asdimethyl formamide, and if required further modifying the resultingproduct.

For example, if the esterification product is itself an ester, such canbe converted to the carboxylic acid, e.g. by hydrogenolysis of aresulting benzyl ester. Also if the esterification product is itself ahalide, such can for instance be converted to the nitrooxy derivative byreaction with e.g. silver nitrate.

For example, the compounds of formula Ia are preferably prepared bycondensing a salt of a carboxylic acid of formula I above with acompound of formula

X—CH₂COOR_(a)

wherein X is a leaving group and R_(a) is a carboxy protecting group toobtain a compound of formula la in carboxy protected form, andsubsequently removing the protecting group R_(a).

The esterification can be carried under esterification conditions knownin the art, e.g. in a polar solvent such as dimethylformamide, at atemperature range of room temperature to about 100° C., preferably at arange of 40-60° C.

The salt of the acid of formula I is preferably an alkali metal salt,e.g. the sodium salt which may be prepared in situ.

Leaving group X is preferably halo, e.g. chloro or bromo, or loweralkylsulfonyloxy, e.g. methanesulfonyloxy.

Carboxy protecting group R_(a) is preferably benzyl.

The resulting benzyl esters can be converted to the free acids offormula Ia preferably by hydrogenolysis with hydrogen in the presence ofe.g. Pd/C catalyst in acetic acid at atmospheric pressure or under Parrhydrogenation at a temperature ranging from room temperature to about50° C.

The invention includes any novel starting materials and processes fortheir manufacture.

Finally, compounds of the invention are either obtained in the freeform, or as a salt thereof if salt forming groups are present.

The acidic compounds of the invention may be converted into metal saltswith pharmaceutically acceptable bases, e.g. an aqueous alkali metalhydroxide, advantageously in the presence of an ethereal or alcoholicsolvent, such as a lower alkanol. Resulting salts may be converted intothe free compounds by treatment with acids. These or other salts canalso be used for purification of the compounds obtained. Ammonium saltsare obtained by reaction with the appropriate amine, e.g. diethylamine,and the like.

Compounds of the invention having basic groups can be converted intoacid addition salts, especially pharmaceutically acceptable salts. Theseare formed, for example, with inorganic acids, such as mineral acids,for example sulfuric acid, a phosphoric or hydrohalic acid, or withorganic carboxylic acids, such as (C₁-C₄)alkanecarboxylic acids which,for example, are unsubstituted or substituted by halogen, for exampleacetic acid, such as saturated or unsaturated dicarboxylic acids, forexample oxalic, succinic, maleic or fumaric acid, such ashydroxycarboxylic acids, for example glycolic, lactic, malic, tartaricor citric acid, such as amino acids, for example aspartic or glutamicacid, or with organic sulfonic acids, such as (C₁-C₄)-alkylsulfonicacids (for example methanesulfonic acid) or arylsulfonic acids which areunsubstituted or substituted (for example by halogen). Preferred aresalts formed with hydrochloric acid, methanesulfonic acid and maleicacid.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal, topical, andparenteral administration to mammals, including man, to inhibitCOX-2-activity, and for the treatment of COX-2 dependent disorders, andcomprise an effective amount of a pharmacologically active compound ofthe invention, alone or in combination, with one or morepharmaceutically acceptable carriers.

More particularly, the pharmaceutical compositions comprise an effectivecyclooxygenase-2 inhibiting amount of a selective cyclooxygenase-2inhibiting compound of the invention which is substantially free ofcyclooxygenase-1 inhibiting activity and of side effects attributedthereto.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients or carrierssuitable for either enteral or parenteral application. Preferred aretablets and gelatin capsules comprising the active ingredient togetherwith a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol; fortablets also c) binders e.g. magnesium aluminum silicate, starch paste,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose andor polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, or effervescent mixtures; and/ore) absorbents, colorants, flavors and sweeteners. Injectablecompositions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Said compositions are prepared according toconventional mixing, granulating or coating methods, respectively, andcontain about 0.1 to 75%, preferably about 1 to 50%, of the activeingredient.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable formulations for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Suitable formulations for topical application, e.g. to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, for example, for delivery by aerosol or thelike. Such topical delivery systems will in particular be appropriatefor dermal application, e.g. for the treatment of skin cancer, forexample, for prophylactic use in sun creams, lotions, sprays and thelike. In this regard it is noted that compounds of the present inventionare capable of absorbing UV rays in the range of 290-320 nm whileallowing passage of tanning rays at higher wavelengths. They are thusparticularly suited for use in topical, including cosmetic, formulationswell-known in the art. Such may contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives. Formulationssuitable for topical application can be prepared e.g. as described inU.S. Pat. No. 4,784,808. Formulations for ocular administration can beprepared e.g. as described in U.S. Pat. Nos. 4,829,088 and 4,960,799.

The pharmaceutical formulations contain an effective COX-2 inhibitingamount of a compound of the invention as defined above, either alone orin combination with another therapeutic agent.

For example, suitable additional active agents for use in relation tothe treatment of neoplasia include e.g. any of the anti-neoplasticagents or radioprotective agents recited in International patentapplication WO 98/16227.

In conjunction with another active ingredient, a compound of theinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

The dosage of active compound administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration. A unit dosage for oraladministration to a mammal of about 50 to 70 kg may contain betweenabout 5 and 500 mg, of the active ingredient.

The present invention also relates to methods of using the compounds ofthe invention and their pharmaceutically acceptable salts, orpharmaceutical compositions thereof, in mammals for inhibiting COX-2 andfor the treatment of COX-2 dependent conditions as described herein,e.g. inflammation, pain, rheumatoid arthritis, osteoarthritis, ocularinflammatory disorders, glaucoma and dry eye disease.

Particularly the present invention relates to a method of selectivelyinhibiting cyclooxygenase-2 activity in a mammal without substantiallyinhibiting cycloxygenase-1 activity which comprises administering to amammal in need thereof an effective cyclooxygenase-2 inhibiting amountof a compound of the invention.

Thus the present invention also relates to a method of treatingcyclooxygenase-2 dependent disorders in mammals, which comprisesadministering to a mammal in need thereof an effective cyclooxygenase-2inhibiting amount of a compound of the invention.

More particularly the present invention relates to a method of treatingcyclooxygenase-2 dependent disorders in mammals while substantiallyeliminating undesirable side effects associated with cyclooxygenase-1inhibiting activity which comprises administering to a mammal in needthereof an effective cyclooxygenase-2 inhibiting amount of a selectivecyclooxygenase-2 inhibiting compound of the invention which issubstantially free of cyclooxygenase-1 inhibiting activity.

More specifically such relates to a method of e.g. treating rheumatoidarthritis, osteoarthritis, pain or inflammation in mammals withoutcausing undesirable gastrointestinal ulceration, which method comprisesadministering to a mammal in need thereof a correspondingly effectiveamount of a compound of the invention.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100 mmHg (=20-133 mbar). The structure of final products, intermediates andstarting materials is confirmed by standard analytical methods, e.g.microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR).Abbreviations used are those conventional in the art.

EXAMPLE 1

(a)N,N-dimethyl-5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetamide(1.5 g, 4.3 mmol) is hydrolyzed with 6N NaOH (70 ml) as a two phasesolution with n-BuOH (40 ml) at reflux temperature for 14 hours. Aftercooling to room temperature, the mixture is poured over ice (100 ml).Toluene (100 ml) is added and the mixture transferred to a separatoryfunnel. The aqueous phase is brought to a pH of 1 with 3 N HCl. Theorganic phase is separated and the aqueous phase re-extracted withtoluene (100 ml). The combined organic solution is dried (MgSO₄) andconcentrated under high vacuum (35-50 mbar), on a rotovap, taking carenot to warm above 50°. Upon crystallization from Et₂O/hexane,5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetic acid isobtained as a tan solid, m.p. 137-141°.

The starting material,N,N-dimethyl-5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetamideis prepared in the following manner:

5-Methyl-2-iodobenzoic acid (100 g, 0.38 mol) is dissolved in THF (350ml) and cooled in an ice bath. Borane-THF complex (380 ml of 1M in THF,0.38 mol) is added dropwise. After addition is complete, the reaction iswarmed to room temperature and stirred for 14 hours. The mixture istransferred to a large erienmeyer flask, cooled in an ice bath, andcarefully quenched with water (250 ml). Evaporation of the THF on arotovap gives a white suspension which is treated with additional water(1 L) and then filtered and dried in a vacuum dessicator over P₂O₅ togive 2-iodo-5-methylbenzyl alcohol as a white solid, m.p. 82-85°.

The benzylic alcohol (99.8 g, 0.38 mol) is dissolved in 48% HBr (500 ml)and heated to reflux temperature for 4 hours. The resulting benzylicbromide is isolated as a yellow solid by pouring the cooled mixture intoa large volume (1.5 L) of water followed by filtration. The benzylicbromide (caution: lachrymator) is dissolved in EtOH (400 ml) and stirredat room temperature. Sodium cyanide (56 g, 1.14 mol) is dissolved in aminimum amount (˜100 ml) of water and then added to the ethanolicsolution of the benzylic bromide. The reaction is heated to refluxtemperature for 3 hours and then cooled to room temperature. Ethanol isremoved on a rotovap and the residue washed with a large volume (1 L) ofwater. The resulting 2′-iodo-5′-methylphenylacetonitrile is isolated asa white solid, m.p. 77-790°, by filtration.

The nitrile (94.5 g, 0.37 mol) is dissolved in EtOH (350 ml) and treatedwith NaOH (29.4 g, 0.74 mol) which has been dissolved in water (200 ml).The reaction is heated to reflux temperature for 14 hours. After coolingto room temperature, ethanol is removed on a rotovap and 6N HCl addeduntil the pH=1. The solid 5-methyl-2-iodophenylacetic acid is filteredoff and washed with water (2×500 ml). After drying over P₂O₅ in a vacuumdessicator, the solid 5-methyl-2-iodophenyl acetic acid (mp 112-114°, 83g, 0.30 mol) is dissolved in CH₂Cl₂ (450 ml) that contains several dropsof DMF. To the solution thionyl chloride (32 ml, 0.450 mol) is added andthe reaction heated to reflux temperature overnight. After cooling toroom temperature, the reaction mixture is diluted with additional CH₂Cl₂(500 ml) and washed with water (2×250 ml), saturated NaHCO₃ (250 ml) andbrine (250 ml). The solution is dried (MgSO₄) and concentrated on arotovap to give 5-methyl-2-iodophenylacetyl chloride as a yellowish oil.

Dimethylamine (200 ml of 2 M solution in THF) is added dropwise to asolution of 5-methyl-2-iodophenylacetyl chloride in Et₂O (500 ml) whichis cooled in an ice bath. After the addition is complete, EtOAc (350 ml)is added and the solution is washed with water (350 ml), brine (250 ml)and dried (MgSO₄). Evaporation on a rotovap and trituration with 1:1Et₂O/hexanes gives N,N-dimethyl-5-methyl-2-iodophenylacetamide as alight tan solid, m.p. 47-49°.

N,N-Dimethyl-5-methyl-2-iodophenylacetamide (3.5 g, 11.5 mmol) and2,4-dichloro-6-methylaniline (4.1 g, 23 mmol) are stirred in xylenes(100 ml) with copper powder (0.18 g, 2.9 mmol), copper(l) iodide (0.55g, 2.9 mmol) and anhydrous potassium carbonate (1.6 g, 11.5 mmol). Thereaction is heated to reflux temperature for 48 hours. While stillslightly warm (40°) the brown suspension is filtered through a pad ofCelite, which in turn is rinsed with toluene (75 ml). The filtrate isevaporated on a rotovap and flash chromatographed on silica gel (R_(f)0.30 in 40% EtOAc/hexane) to giveN,N-dimethyl-5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetamide as an off-white crystalline solid, m.p. 119-124°.

Similarly prepared are:

(b) 5-methyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid, m.p.153-156°;

(c) 5-methyl-2-(2′,6′-dichloroanilino)phenylacetic acid, m.p.168-170°;

potassium salt, m.p. 318-320°; sodium salt, m.p. >300°;

(d) 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid, m.p.158-159°;

(e) 5-methyl-2-(2′,6′-dichloro-4′-methylanilino)phenylacetic acid, m.p.179-182°;

(f) 5-methyl-2-(2′-chloro-6′-methylanilino)phenylacetic acid, m.p.138-140°;

(g) 5-methyl-2-(2′,4′-difluoro-6′-chloroanilino)phenylacetic acid, m.p.157-159°;

(h) 5-methyl-2-(2′-fluoro-4′,6′-dichloroanilino)phenylacetic acid, m.p.178-180°;

(i) 5-methyl-2-(2′-chloro-4′-fluoro-6′-methylanilino)phenylacetic acid,m.p. 154-156°.

(j) 5-methyl-2-(2′-chloro-4′-hydroxy-6′-fluoroanilino)phenylacetic acid,m.p. 180-182°.

The starting material for compound of Example 1(j),2-chloro-4-pivaloyloxy-6-fluoroaniline, is prepared in the followingmanner:

To a mixture of 7.0 g (0.045 mol) of 3-fluoro-4-nitrophenol and 6.7 g(0.067 mol) of triethylamine in 20 ml of methylene chloride cooled to 0°is added 6.5 g (0.054 mol) of pivaloyl chloride in a dropwise manner.The reaction is allowed to warm to room temperature and stirredovernight. The reaction is quenched with water and extracted with ethylacetate. The organic layer is washed successively with 1 N hydrochloricacid, saturated aqueous sodium bicarbonate, and saturated brine, andthen dried over magnesium sulfate. Filtration and removal of thesolvents gives crude 2-fluoro-4-pivaloyloxy-nitrobenzene which isdissolved in 200 ml of absolute ethanol. To the solution is added 0.9 gof 5% palladium on carbon, and the mixture is then hydrogenated under 30psi hydrogen for two hours. The catalyst is filtered and the solventremoved to give 2-fluoro-4-pivaloyloxyaniline.

A mixture of 7.3 g (0.035 mol) of 2-fluoro-4-pivaloyloxyaniline and 5.1g (0.038 mol) of N-chlorosuccinimide in 50 ml of fluorobenzene is heatedto reflux under a nitrogen atmosphere for two hours. After cooling toroom temperature, the solvent is removed, water is added, and themixture is extracted with ethyl acetate. The organic layer is washedwith 1 N sodium hydroxide, and saturated brine, and dried over magnesiumsulfate. Filtration and removal of the solvents gives a residue which ispurified by silica gel chromatography (20% ethyl acetate/hexane) to give2-chloro-4-pivaloyloxy-6-fluoroaniline. Conversion of2-chloro-4-pivaloyloxy-6-fluoroaniline to5-methyl-2-(2′-chloro-4′-hydroxy-6′-fluoroanilino)phenylacetic acid iscarried out in a manner similar to that described in Example 1, thepivaloyl group being hydrolyzed in the last step along with thedimethylamide to give the final product.

EXAMPLE 2

Similarly prepared according to procedures described in Example 1 are:

(a) 5-ethyl-2-(2′-fluoro-6′-chloroanilino)phenylacetic acid, m.p.147-148°;

The starting material, 5-ethyl-2-iodo-N,N-dimethylphenylacetamide isprepared as follows:

AlCl₃ (303 g, 2.27 mol) is placed in a 3-necked flask fitted with athermometer and a dropping funnel. While stirring DMF (50 ml) is addeddropwise and the temperature rises to about 60°. The mixture is cooleddown to 45°, and oxindole (33 g, 0.25 mol) is added in 3 portions. Afteran additional 10 minutes, acetyl chloride (36 ml, 0.5 mol) is added. Themixture is stirred for an additional 30 minutes at room temperature. Themixture is poured onto ice (3000 g). This results in the formation of asolid which is filtered off, washed first with water and then with coldmethanol (1000 ml), and then dried to give 5-acetyloxindole.

The 5-acetyloxindole (54 g, 308 mmol), acetic acid (400 ml) andpalladium on carbon (10%, 5 g) are combined and treated with hydrogenfor 14 hours at 55 psi. The catalyst is removed by filtering through abed of Celite, the filtrate is concentrated under reduced pressure andthe residue is treated with ether to give 5-ethyloxindole

5-Ethyloxindole (˜54 g, ˜335 mmol), ethanol (750 ml), water (150 ml) andpotassium hydroxide (65 g, 1.62 mol) are combined and heated at refluxfor 3 days. The mixture is allowed to cool and then filtered through abed of Celite. The filtrate is concentrated under reduced pressure,water is added and the pH adjusted to 6.5. The precipitate is filteredoff, washed with water and dried in an oven overnight to yield5-ethyl-2-aminophenylacetic acid.

A mixture of water (405 ml) and concentrated HCl (48 ml) is stirred andcooled to 0°. 5-Ethyl-2-aminophenylacetic acid (53.7 g, 300 mmol) isslowly added while maintaining the temperature at 0-2°. After thisaddition a solution of sodium nitrite (22.2 g, 322 mmol) in 60 ml wateris added dropwise over 30 minutes keeping the temperature at 0-2°. Aftera further 20 minutes a solution of potassium iodide (48 g, 290 mmol) in18 ml conc HCl and 130 ml water is added dropwise while keeping thetemperature below 10° C. The reaction mixture is allowed to warm to roomtemperature and then heated to reflux for 2 hours. The mixture isextracted with ethyl acetate and ether (1:1 mixture, 4×300 ml), theorganic layer is then washed first with a 30% aqueous solution of sodiumthiosulfite and then with a sodium hydroxide solution (0.1 M) beforebeing acidified to pH 6 and extracted with ethyl acetate. This solutionis washed with saturated brine, dried (magnesium sulfate), filtered, andthe solvent removed under reduced pressure. The residue is treated withhexane to yield 5-ethyl-2-iodophenylacetic acid.

5-Ethyl-2-iodophenylacetic acid is dissolved in methylene chloride (400ml) and DMF (1 ml) is added. Thionyl chloride (21 ml, 300 mmol) is thenadded dropwise over 20 minutes. The mixture is heated to reflux andheating continued for 3.5 hours when the mixture is cooled and ice-water(400 ml) and methylene chloride (300 ml) are added. The layers areseparated, the organic layer is washed with a sodium bicarbonatesolution, saturated brine, dried (magnesium sulfate), and evaporatedunder reduced pressure to yield 5-ethyl-2-iodophenylacetyl chloride.

The acid chloride (46 g 150 mmol) is dissolved in ether (500 ml) andstirred at −35°. Dimethylamine (250 ml of 2M solution in THF, 500 mmol)is added dropwise at −35° and the mixture allowed to warm to roomtemperature and then stirred for 60 hours. Ethyl acetate and water areadded and the layers separated. The organic layer is washed withsaturated brine and the combined aqueous layers washed with ether. Thecombined organic layers are now dried (magnesium sulfate), and thesolvent is removed under reduced pressure. Hexane is added to yieldN,N-dimethyl 5-ethyl-2-iodophenylacetamide as a solid.

(b) 5-ethyl-2-(2′-chloro-6′-methylanilino)phenylacetic acid, m.p.125-126°;

(c) 5-ethyl-2-(2′,3′,6′-trifluoroanilino)phenylacetic acid, m.p.138-140°;

(d) 5-ethyl-2-(2′,3′,5′,6′-tetrafluoro 4′-ethoxyanilino)phenylaceticacid, m.p. 131-132°;

(e) 5-ethyl-2-(2′-chloro-4′,6′-difluoroanilino)phenylacetic acid, m.p.160-162°;

(f) 5-ethyl-2-(2′,4′-dichloro-6′-fluoroanilino)phenylacetic acid,m.p.169-171°.

EXAMPLE 3

(a)N,N-Dimethyl-5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide(26 g, 0.073 mol) and 6N NaOH (150 ml) are stirred as a two phasesolution with n-BuOH (150 ml) at reflux temperature for 14 hours. Aftercooling to room temperature, the reaction is poured over ice (500 ml).Toluene (500 ml) is added and the mixture transferred to a separatoryfunnel. The aqueous phase is brought to a pH of 1 with 3 N HCl. Theorganic layer is separated and the aqueous phase re-extracted withtoluene (250 ml). The combined organic layers are dried (MgSO₄) andconcentrated under high vacuum (35-50 mbar) on a rotovap taking care notto warm above 500°. Small white needles are obtained by crystallizationof the residue from hexane, m.p. 164-166°. Recrystallization fromcyclohexane gives 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid a white solid, m.p. 165-169°.

The starting materialN,N-dimethyl-5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamideis prepared in the following manner

N,N-Dimethyl-2-iodophenylacetamide (60 g, 0.208 mol),2′,3′,5′,6′-tetrafluoroaniline (100 g, 0.606 mol), copper powder (6.6 g,0.104 mol), copper(I) iodide (19.8 g, 0.104 mol) and anhydrous potassiumcarbonate (28.7 g, 0.208 mol) are stirred together in 1000 ml ofxylenes. The reaction is heated to reflux temperature for 48 hours.While still slightly warm (40°) the brown suspension is filtered througha pad of Celite which in turn is rinsed with toluene (250 ml). Thefiltrate is evaporated on a rotovap and then flash chromatographed onsilica-gel (Rf 0.25 in 30% EtOAc/hexane). Crystallization frompentane/Et₂O givesN,N-dimethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide, m.p.109-110°.

Under an inert atmosphere, acetyl chloride (29.1 ml, 0.385 mol) isslowly added to a suspension of aluminum chloride (51.2 g, 0.385 mol)stirred in 1,2-dichloroethane (750 ml). After stirring at roomtemperature for 1 hour a yellow solution is obtained. The solution iscooled in an ice bath andN,N-dimethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide (40 g,0.123 mol) is added.

The reaction is allowed to warm to room temperature and then warmed to800° for 0.5 hours. The reaction is poured over ice and extracted withEtOAc (2×750 ml). The organic extract is washed with water (750 ml),saturated NaHCO₃ solution (500 ml) and brine (500 ml). Evaporation on arotovap and trituration with Et₂O givesN,N-dimethyl-5-acetyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamideas a white solid, m.p. 112-114°.

N,N-dimethyl-5-acetyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide(30 g, 0.802 mol) is dissolved in HOAc (150 ml) and hydrogenated (55psi) with a 10% Pd/C (1.5 g) catalyst for 8 hours. The catalyst isremoved by filtration through Celite and the filtrate poured into water(500 ml) and EtOAc (500 ml). The organic layer is washed with water (750ml), neutralized with saturated Na₂CO₃ solution (500 ml) and washed withbrine (500 ml). Evaporation on a rotovap followed by trituration withhexanes givesN,N-dimethyl-5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide,m.p. 105-106°.

Similarly prepared are:

(b) 5-ethyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetic acid, m.p.180-183°;

(c) 5-ethyl-2-(2′,6′-dichloroanilino)phenylacetic acid, m.p. 133-136°.

EXAMPLE 4

(a) N-(2,3,5,6-tetrafluorophenyl)-5-ethyloxindole (72.67 g; 0.235 mol,is slurried in water containing a little methanol (10% v/v; 253 ml), andsodium hydroxide solution (50 wt %; 16.1 ml) is added. The mixture isstirred at 80-85° for 2-4 hours, then cooled to ambient temperature. Thereaction solution is partially concentrated under reduced pressure(25-30 mm). After removal of 50 ml of the solvent, the mixture isdiluted with water (150 ml) and t-butyl methyl ether (250 ml). Thecooled mixture is acidified to pH 6.5-7.0 with aqueous HCI (12.1 N; 19.5ml), keeping the temperature at 0-5°. The aqueous layer is discarded andthe organic layer is washed with water (250 ml). The organic layer isconcentrated under reduced pressure (20-100 mm) while exchanging thesolvent to toluene. After the more volatile components have beenremoved, the batch volume is adjusted to 400-450 ml. This mixture iswarmed to 700°, clarified, concentrated to one-half volume, and cooledto 0° After stirring at this temperature for 2 hours, the product iscollected and is washed with toluene/heptane (10:90; 100 ml). Theresulting solid is dried under reduced pressure at 50-60° for 4-8 hoursto give 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid ofExample 3.

The starting material is prepared as follows: 4-Ethylaniline (242.36 g;2.00 mol) is dissolved in dry tetrahydrofuran (900 ml). A solution ofn-BuLi (2.5 M in hexanes, 800 ml; 2.00 mol) is added under N₂ withcooling maintaining the reaction temperature below 15°. After stirringfor 1 hour at 10°, neat pentafluorobenzene (168.06 g; 1.00 mol) is addedwith cooling to the mixture, keeping the temperature at 10-200. Thereaction is stirred at ambient temperature for 1.5 hours, then aqueousHCl (6 N; 500 ml) is added slowly with vigorous stirring and cooling,keeping the reaction temperature below 350°. The quenched reaction isstirred at ambient temperature for 0.5-18 hours. The aqueous layer isseparated, and the organic phase is concentrated under reduced pressure(30-150 mm) to one-fourth volume. The concentrate is diluted withheptane (300 ml) and extracted with water (300 ml). The separated toporganic layer is stirred over 230-400 mesh silica gel (50 g) andfiltered. The filter cake is washed with heptane (4×50 ml). The combinedfiltrate and washings are concentrated under reduced pressure (20-30 mm)to give solid crude product. This material is recrystallized from hotheptane (200 ml) and collected at 0°. This solid is washed with coldheptane (100 ml) and dried under reduced pressure at 400 to give pureN-(2′,3′,5′,6′-tetrafluorophenyl)4-ethylaniline.

The diphenylamine derivative (230.0 g; 0.854 mol; 1.0 eq) is treatedwith chloroacetyl chloride (192.96 g; 1.709 mol; 2.0 eq) at 100-115° for2 hours (vigorous HCl evolution is controlled by rate of heating). Themixture is cooled to ambient temperature, then concentrated underreduced pressure (10-12 mm) to 80-90% of the original volume.1,2-Dichlorobenzene (80 ml) is added and the diluted mixture isconcentrated under reduced pressure (10-12 mm) until no morechloroacetyl chloride is found by GC analysis (30-40 ml distilled) togive crudeN-(2′,3′,5′,6′-tetrafluorophenyl)-N-chloroacetyl-4-ethylaniline insolution.

Anhydrous AIC₃ (170.84 g; 1.281 mol; 1.5 eq) was slurried with1,2-dichlorobenzene (480 ml) under N₂ and cooled to 0°. The crudeproduct solution from the previous step (theoretically containing 295.34g; 0.854 mol; 1.0 eq) is added slowly with vigorous stirring, keepingthe temperature below 60°. A solution of EtAlCl₂ (1.8M in toluene; 733ml; 1.319 mol; 1.7 eq) is added, and the vigorously stirred reactionmixture is heated to ˜160°, distilling toluene (135-160°) at ambientpressure. Upon cessation of the distillation (˜690 ml), the reactiontemperature is held at 155-165° for 3.5-5 hours. The mixture is cooledto ambient temperature, then poured onto crushed ice (2.5 kg) withvigorous stirring under N₂. The reaction vessel is rinsed with1,2-dichlorobenzene (50 ml). The cold quenched product slurry isfiltered and the filtercake is washed sequentially with 10%1,2-dichlorobenzene/heptane (100 ml) and heptane (100 ml). The materialis dried under reduced pressure at 80-90° for 12-16 hours to giveN-(2′,3′,5′,6′-tetrafluorophenyl)-5-ethyloxindole.

EXAMPLE 5

(a) N,N-Dimethyl5-ethyl-2-(4′-chloro-2′-fluoro-6′-methylanilino)phenylacetamide isconverted as in the previous examples to5-ethyl-2-(4′-chloro-2′-fluoro-6′-methylanilino)phenylacetic acid, m.p.153-156°.

The starting material is prepared as follows:

Ullmann condensation of N,N-dimethyl-5-ethyl-2-iodo-phenylacetamide with2-bromo-4-chloro-6-fluoroaniline according to the procedure described inExample 1 yieldsN,N-dimethyl-5-ethyl-2-(2′-bromo-4′-chloro-6′-fluoroanilino)phenylacetamide.

N,N-Dimethyl-5-ethyl-2-(2′-bromo-4′-chloro-6′-fluoroanilino)phenylacetamide(2.5 g, 6.0 mmol) is combined with DMF (10 ml), triethylamine (10 ml),tri-o-tolylphosphine (0.5 g, 1.6 mmol), tetramethyltin (4 ml, 5.16g,28.9 mmol) and palladium acetate (0.25 g, 1.1 mmol), and the mixtureheated in a sealed tube for 3 days at 95°. The tube is allowed to cooland carefully opened. Water and ethyl acetate are added to the reactionand the mixture separated. The organic fraction is washed with a diluteNaCl solution (2×50 ml). The combined aqueous fractions are then washedwith ethyl acetate and the combined organic fractions are then dried(magnesium sulfate). The material is absorbed onto a small amount ofsilica gel and purified by flash chromatography (on silica, ethylacetate:hexanes, 1:4 to 1:1) to giveN,N-dimethyl-5-ethyl-2-(4′-chloro-2′-fluoro-6′-methylanilino)phenylacetamide.

Similarly prepared are:

(b) 5-ethyl-2-(2′,4′-difluoro-6′-methylanilino)phenylacetic acid, m.p.143-145°;

(c) 5-ethyl-2-(2′-chloro-4′-fluoro-6′-methylanilino) phenylacetic acid,m.p. 151-154°;

EXAMPLE 6

(a) 5-Ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid (1.0 g,3.06 mmol) in THF (100 ml) is treated with 1 N sodium hydroxide (3.06ml, 3.06 mmol) for 1 hour. The mixture is concentrated on a rotovap andthen dried by evaporating first with THF (2×100 ml) and then withbenzene (2×100 ml). The remaining off-white sodium salt of5-ethyl-2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid is dried underhigh vacuum overnight. Sodium5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetate (0.5 g, 1.43mmol) and benzyl 2-bromoacetate (272 μl, 1.72 mmol) are stirred at 50°in dimethylformamide (50 ml) for 14 hours. The reaction mixture iscooled to room temperature and partitioned between EtOAc (200 ml) andwater (200 ml). The organic layer is washed again with water (2×200 ml),brine (100 ml), dried (MgSO₄) and concentrated on a rotovap. The crudebenzyl ester is flash chromatographed on silica (10-15% EtOAc/hexane) toprovide the benzyloxycarbonylmethyl ester of5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid as acolorless oil. The oil is dissolved in HOAc (20 ml) and hydrogenated (55psi) with a 10% Pd/C (0.1 g) catalyst for 1 hour. The catalyst isremoved by filtration through Celite and the filtrate poured into water(200 ml) and EtOAc (200 ml). The organic layer is washed with water (250ml) and brine (100 ml). Evaporation on a rotovap and trituration withEt₂O/hexanes gives the ester, carboxymethyl5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino) phenylacetate, m.p. 151-153°,of the formula

Similarly prepared are:

(b) carboxymethyl5-ethyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetate, m.p. 123-125°;

(c) carboxymethyl 5-ethyl-2-(2′,6′-dichloroanilino)phenylacetate,m.p.124-126°;

(d) carboxymethyl5-ethyl-2-(2′,4′-difluoro-6′-chloroanilino)phenylacetate, m.p.142-144°;

(e) carboxymethyl5-ethyl-2-(2′,4′-dichloro-6′-fluoroanilino)phenylacetate, m.p. 132-134°;

(f) carboxymethyl 5-ethyl-2-(2′-chloro-6′-fluoroanilino)phenylacetate,m.p. 106-108°;

(g) carboxymethyl5-methyl-2-(2′-fluoro-4′,6′-dichloroanilino)phenylacetate, m.p.148-150°;

(h) carboxymethyl 5-methyl-2-(2′,6′-dichloroanilino)phenylacetate, m.p.125-126°;

(i) carboxymethyl 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetate,m.p. 96-98°.

(j) carboxymethyl5-methyl-2-(2′,4′-difuoro-6′-chloroanilino)phenylacetate.

EXAMPLE 7

5-Ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid (1.0 g, 3.06mmol) in THF (100 ml) is treated with 1 N sodium hydroxide (3.06 ml,3.06 mmol) for 1 hour. The mixture is concentrated on a rotovap and theresidue is then treated and evaporated to dryness first with THF (2×100ml) and then with benzene (2×100 ml). The remaining off-white sodiumsalt of 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid isdried under high vacuum overnight.

The sodium 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino) phenylacetate (2.0g, 6.2 mmol) is dissolved in DMF (70 ml) and treated with 1-bromo-4-chlorobutane (1.2 g, 6.9 mmol) at room temperature overnight. Thereaction mixture is concentrated under high vacuum (35-50 mbar) on arotovap. The resulting oil is partitioned between water (200 ml) andEt₂O (200 ml). The organic layer is washed with brine (100 ml), dried(MgSO₄) and concentrated on a rotovap to give the chlorobutyl ester as alight-brown oil. The chlorobutyl ester is dissolved in CH₃CN (100 ml)and treated with silver nitrate (8.7 g, 50 mmol) at reflux temperaturefor 18 hours. The reaction is cooled to room temperature and the solventremoved on a rotovap. The residue is partitioned between CH₂Cl₂ (200 ml)and water (200 ml). The organic layer is dried (MgSO₄), concentrated andflash-chromatographed (5% EtOAc/hexane) to give nitrooxybutyl5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetate as a clear oil.

EXAMPLE 8

Sodium 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetate (7.3 g,20.9 mmol) is dissolved DMF (100 ml) and treated with benzyl2-methyl-2-bromopropionate (6.2 g, 24.2 mmol) at 500 for 96 hours. Thereaction mixture is cooled to room temperature, and concentrated underhigh vacuum (35-50 mbar) on a rotovap. The resulting oil is partitionedbetween water (200 ml) and Et₂O (200 ml). The organic layer is washedwith brine (100 ml), dried (MgSO₄) and concentrated on a rotovap to givea light-brown oil. Flash chromatography (0-10% EtOAc/hexane) onsilica-gel gives the ester as a light-red oil. The ester (1.5 g, 3.0mmol) is dissolved in EtOAc (150 ml) and hydrogenated (55 psi) with a10% Pd/C (0.3 g) catalyst for 1 hour. The catalyst is removed byfiltration through Celite (500 ml). Evaporation on a rotovap followed bytrituration with hexanes gives 1-carboxy-1-methylethyl5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetate as a crystallinewhite solid, m.p. 104-108°.

EXAMPLE 9

(a) Isopropyl5-methyl-2-(2′-fluoro-6′-trifluoromethylanilino)phenylacetate (2.9 g,8.4 mmol) is dissolved in methanesulfonic acid (25 ml) and stirred atroom temperature for 8 hours. The reaction mixture is slowly added to200 ml of ice in a beaker. After the ice has melted, the solution isstirred to produce a white solid which is isolated by filtration. Thesolid is flash chromatographed on silica-gel using 35% EtOAc as aneluant to give5-methyl-2-(2′-fluoro-6′-trifluoromethylanilino)phenylacetic acid as awhite solid, m.p. 155-156°.

The starting material is prepared as follows:

2-Iodo-5-methylphenylacetic acid (20.0 g, 72 mmol) and a catalyticamount of 98% sulfuric acid (0.2 ml) are dissolved in isopropyl alcohol(200 ml) and heated to reflux temperature for 48 hours. The solvent isremoved on a rotovap and the residual oil partitioned between EtOAc (500ml) and saturated NaHCO₃ solution (500 ml). The organic layer isseparated, dried (MgSO₄) and concentrated on a rotovap. The residual oilis distilled using a kugelrohr apparatus to give a clear, colorless oilwhich solidifies on standing at room temperature to give isopropyl2-iodo-5-methylphenylacetate, m.p. 48-50°.

Isopropyl 2-iodo-5-methylphenylacetate (10.0 g, 31 mmol),2-amino-3-fluorobenzotrifluoride (20.0 g, 111 mmol), copper powder (1.1g, 16 mmol), copper (I) iodide (3.1 g, 16 mmol) and K₂CO₃ (4.3 g, 31mmol) are stirred together in xylenes (200 ml). The reaction mixture isheated to reflux temperature for 48 hours. While still slightly warm(400) the brown suspension is filtered through a pad of Celite, which inturn is rinsed with toluene (100 ml). The filtrate is evaporated on arotovap and then flash chromatographed on silica-gel using 34% EtOAc inhexanes as the eluant. The product, isopropyl5-methyl-2-(2′-fluoro-6′-trifluoromethylanilino)phenyl acetate, isisolated as a pale yellow oil.

(b) Similarily prepared is5-methyl-2-(2′,4′-dichloro-6′-trifluoromethylanilino)phenylacetic acid,m.p. 157-158°.

EXAMPLE 10

(a) To a degassed solution of 1500 ml of absolute ethanol and 510 ml of2N NaOH (1.02 mol) is added 150 g (0.51 mol) ofN-(2′-chloro-4′,6′-difluorophenyl)-5-methyloxindole. The resultantmixture is degassed and heated to 60-65° for 2 hours. Most of theethanol is removed under reduced pressure and then 4500 ml of water isadded to the residue which is then washed three times with 1500 ml oftoluene. The aqueous layer is cooled to 0° and adjusted to pH 6 using1.2 N HCl. The solid is filtered off and washed with 100 ml of water anddried. Recrystallization from ethyl acetate and heptane gives5-methy-2-(2′,4′-difluoro-6-chloroanilino)phenylacetic acid of Example1(g).

The starting material is prepared in the following manner:2-Bromo-4,6-difluoroaniline (26.00 g; 0.13 mol) is added to 78 ml (0.71mol) of acetic anhydride and stirred at room temperature for 5 hours.The reaction is quenched by the addition of 104 ml of water over a 10minute period, causing the temperature to rise to 43°. The reaction isallowed to cool to room temperature and then cooled to 5° in ice water.The solids are collected by suction filtration, washed with 104 ml ofwater, and dried to give 2-bromo-4,6-difluoroacetanilide, m.p. 156°.

Cuprous chloride (11.9 g, 0.12 mol) and cupric chloride (16.14 g, 0.12mol) are dissolved in 100 ml of DMF. 2-Bromo-4,6-difluoroacetanilide (20g, 0.08 mol) is added and the solution is heated to 130° C. for 20hours. The reaction is cooled to room temperature and then addeddropwise over 30 minutes to 400 ml of 3N HCl. The solid is filtered off,washed with 200 ml of water, and dried to give2-chloro-4,6-difluoroacetanilide, m.p. 144-150°.

To a slurry of 110.36 g (0.54 mol) of 2-chloro-4,6-difluoroacetanilidein 735 ml of absolute ethanol is added 100.36 ml (1.32 mol) ofconcentrated HCl. The mixture is heated to reflux for 20 hours and thencooled to room temperature. The mixture is concentrated under reducedpressure to give a residue which is dissolved in 1105 ml of water, and1N NaOH is added to adjust the pH to 12. The basic mixture is extractedtwice with ethyl acetate and the combined organic layers are washed with735 ml of water. The solvents are evaporated under reduced pressure togive 2-chloro4,6-difluoroaniline as an oil.

A mixture of 4-iodotoluene (210 g, 0.96 mol),2-chloro-4,6-difluoroaniline (204 g, 1.25 mol), copper powder (36 g,0.57 mol), cuprous iodide (130 g, 0.68 mol), and potassium carbonate(118 g, 0.86 mol) in 500 ml of xylene is stirred vigorously and heatedto reflux in a flask fitted with a Dean-Stark trap for 26 hours. Aftercooling to room temperature, the solids are filtered off, and the filtercake is washed with 100 ml of xylene. The solvents are evaporated underreduced pressure to give an oil which is dissolved in a mixture of 50 gof silica gel in 750 ml of heptane. The solids are filtered off and thesolvents are evaporated under reduced pressure to giveN-(2′-chloro-4′,6′-difluorophenyl)-4-methylaniline as an oil.

A mixture of 230 g (0.9 mol)N-(2′-chloro-4′,6′-difluorophenyl)-4-methylaniline and 325 ml (4.06 mol)of chloroacetyl chloride is heated under a nitrogen atmosphere for onehour at 50°. The solvent is evaporated under reduced pressure to give anoil to which 200 ml of chlorobenzene is added. The solvent is evaporatedunder reduced pressure to completely remove the chloroacetyl chloride,giving N-(2′-chloro4′,6′-difluorophenyl)-N-chloroacetyl-4-methylanilineas an oil.

To a mixture of 100 g (0.3 mol) ofN-(2′-chloro-4′,6′-difluorophenyl)-N-chloroacetyl-4-methylaniline and103 g (0.78 mol) of aluminum chloride is added 400 ml of1,2-dichlorobenzene. The reaction is heated to 140° for 2 hours. Thereaction is cooled to room temperature and added to a mixture of 100 mlof concentrated HCl and 700 ml water (cooled to 0-5° in a dryice/acetone bath). The mixture is extracted twice with 400 ml ofmethylene chloride. The combined organic layers are washed with 600 mlof 3N HCl. The organic layer is stirred with 66 g of magnesium sulfateand 33 g of charcoal (DARCO G-60). The solids are filtered off and thesolvents are evaporated under reduced pressure to give a tan solid whichis recrystallized from ethanol to giveN-(2′-chloro-4′,6′-difluorophenyl)-5-methyloxindole, mp 137-14°.

b) Similarly prepared is5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid of example 1(d).

The preparation of the starting material, N-(2-chloro-6-fluoro)anilinefrom 2-chloro-6-fluorobenzamide is described in Rec. Trav. Chim.Pays-Bas, 97, 51-56 (1978).

EXAMPLE 11

A solution of 1300 ml of ethanol, 130 ml of water and 43.5 g of sodiumhydroxide is degassed. To the solution is added 100.0 g ofN-(2′-chloro-6′-fluorophenyl)-5-methyloxindole and the mixture is heatedto 70° for 2 hours. The reaction is cooled to 50° and 90.7 ml of 37% HClin 453.3 ml of water is added slowly. The suspension is cooled slowly toroom temperature and filtered. The filter cake is washed three timeswith 80 ml of 1:1 ethanol and water and dried to give5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid, m.p. 152-154°.

The starting material, N-(2′-chloro-6′-fluorophenyl)-5-methyloxindole,is prepared in the following manner:

A solution of 261.1 g (2.0 mol) of 1-chloro-3-fluorobenzene in 2000 mlof dry tetrahydrofuran under nitrogen is cooled to −78°. To the solutionis added 960 ml (2.4 mol) of 2.5 M n-butyllithium in hexanes over aperiod of 40 minutes. After stirring for 2.5 hours, a slurry of 155 mlof bromine cooled to −78° is added over 30 minutes and the mixture isstirred for 40 minutes before warming to −10°. The reaction is quenchedwith an aqueous solution of 151.3 g (1.2 mol) of sodium sulfite and 16.0g (0.4 mol) of sodium hydroxide in 500 ml of water. The organic layer isseparated, the solvents are removed at ambient pressure, and the productis distilled at 92-96° (20 mm Hg) to obtain2-bromo-3-fluoro-chlorobenzene as a colorless oil.

A mixture of 146.1 g (1.36 mol) of p-toluidine, 12.6 g (0.02 mol) of(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 261.9 g (2.73 mol) ofsodium t-butoxide, 314.1 g (1.50 mol) of 2-bromo-3-fluoro-chlorobenzeneand 6.3 g (0.0069 mol) of tris(dibenzylideneacetone)dipalladium(0) in3000 ml of toluene is heated to 110° over 30 minutes and stirred anadditional 4 hours at this temperature. The mixture is cooled to roomtemperature and a solution of 680 ml 37% hydrochloric acid and 680 ml ofwater is added over 15 minutes. The mixture is stirred for 20 minutesand filtered through a pad of Celite. The layers are separated and theorganic phase is washed twice with 680 ml of water and once with asolution of 225 g of sodium chloride in 680 ml of water. The solventsare evaporated under reduced pressure to giveN-(2′-chloro-6′-fluorophenyl)-4-methylaniline as an oil, b.p.129-131°/0.5 mm Hg.

A mixture of 25 g (0.11 mol)N-(2′-chloro-6′-fluorophenyl)-4-methylaniline and 40 ml (0.5 mol) ofchloroacetylchloride is heated under a nitrogen atmosphere for 15minutes at 60°. The solvent is evaporated under reduced pressure to givean oil which is dissolved in 25 ml of ethyl acetate. Pentane (250 ml) isadded dropwise over 15 minutes to precipitate the product. The mixtureis cooled to −15° C. and the solid is filtered and washed with pentaneto give N-(2′-chloro-6′-fluorophenyl)-N-chloroacetyl4-methylaniline,m.p. 80-83°.

A mixture of 100 g (0.32 mol) ofN-(2′-chloro-6′-fluorophenyl)-N-chloroacetyl-4-methylaniline and 110 g(0.82 mol) of aluminum chloride in 400 ml of 1,2-dichlorobenzene isstirred vigorously and heated to 140° for 7.5 hours. The reaction iscooled to room temperature and added to a mixture of 100 ml of 12N HCland 700 ml of water (cooled to 0-5° in a dry ice/acetone bath). Themixture is extracted twice with 400 ml of methylene chloride and thecombined organic layers are washed with 600 ml of 3N HCl. The organiclayer is stirred with 66 g of magnesium sulfate and 33 g of charcoal(DARCO G-60). The solids are filtered through a pad of Celite and thesolvents are evaporated under reduced pressure to give a tan solid whichis recrystallized from ethanol to giveN-(2′-chloro-6′-fluorophenyl)-5-methyloxindole, m.p. 137-140°.

Alternatively, a mixture of 169.8 g of crudeN-(2′-chloro-6′-fluorophenyl)-4-methylaniline, 172 ml (2.15 mol) ofchloroacetyl chloride in 580 ml of toluene is heated under a nitrogenatmosphere for 2 hours at 70°. The reaction is cooled to roomtemperature, 450 ml of decane is added, and the volatiles are distilledoff under 200 mbar pressure at 62-72°. To the mixture is added 150 ml oftoluene and 385 g of aluminum chloride (2.87 mol) slowly at 20-40°. Themixture is heated at 120° for 5 hours, cooled to 20°, and added over 30minutes to 800 ml of ethyl acetate. The mixture is quenched by additionto a pre-cooled solution of 67 ml of 37% hydrochloric acid in 800 ml ofwater at 20±10°, and the resultant mixture is filtered through a pad ofCelite. The organic layer is separated and the volatiles are distilledoff. To the residue is added 100 ml of heptane and the mixture is cooledto 0° over a 30 minute period and stirred for one hour. The mixture isfiltered and the filter cake is washed three times with 45 ml ofheptane. To the crude product is added 90 g of charcoal (DARCO G-60) and4500 ml of methanol. The mixture is heated to reflux for two hours,cooled to room temperature, and filtered through a pad of Celite. Afterdistilling off 4390 ml of methanol, the mixture is cooled to 15°. Theproduct is collected by filtration, washed three times with 30 ml ofmethanol, and dried to giveN-(2′-chloro-6′-fluorophenyl)-5-methyloxindole.

What is claimed is:
 1. A compound of formula

wherein R is methyl or ethyl; R₁ is chloro or fluoro; R₂ is hydrogen orfluoro; R₃ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxyor hydroxy; R₄ is hydrogen or fluoro; and R₅ is chloro, fluoro,trifluoromethyl or methyl; or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein R is methyl orethyl; R₁ is chloro or fluoro; R₂ is hydrogen; R₃ is hydrogen, fluoro,chloro, methyl or hydroxy; R₄ is hydrogen; and R₅ is chloro, fluoro ormethyl; or a pharmaceutically acceptable salt thereof.
 3. A compoundaccording to claim 1 wherein R is methyl or ethyl; R₁ is fluoro; R₂ ishydrogen; R₃ is hydrogen, fluoro or hydroxy; R₄ is hydrogen; and R₅ ischloro; or a pharmaceutically acceptable salt thereof.
 4. A compoundaccording to claim 1 wherein R is methyl or ethyl; R₁ is fluoro; R₂ isfluoro; R₃ is hydrogen, ethoxy or hydroxy; R₄ is fluoro; and R₅ isfluoro; or a pharmaceutically acceptable salt thereof.
 5. A compoundaccording to claim 1 wherein R is methyl or ethyl; R₁ is fluoro; R₂ ishydrogen; R₃ is hydrogen or fluoro; R₄ is hydrogen; and R₅ is chloro; ora pharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1 which is carboxymethyl5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetate wherein in formulaI R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is hydrogen; R₄ ishydrogen; and R₅ is chloro; or a pharmaceutically acceptable saltthereof.
 7. A compound according to claim 1 which is carboxymethyl5-methyl-2-(2′,4′-difluoro-6′-chloroanilino)phenylacetate wherein informula I R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is fluoro; R₄ ishydrogen; and R₅ is chloro; or a pharmaceutically acceptable saltthereof.
 8. A compound according to claim 1 which is carboxymethyl5-ethyl-2-(2′,3′,5′,6′,-tetrafluoroanilino)phenylacetate wherein informula I R is ethyl; R₁ is fluoro; R₂ is fluoro; R₃ is hydrogen; R₄ isfluoro; and R₅ is fluoro; or a pharmaceutically acceptable salt thereof.9. A compound according to claim 1 which is carboxymethyl5-ethyl-2-(2′4′-dichloro-6′-methylanilino)phenylacetate wherein informula I R is ethyl; R₁ is chloro; R₂ is hydrogen; R₃ is chloro; R₄ ishydrogen; and R₅ is methyl; or a pharmaceutically acceptable saltthereof.
 10. A pharmaceutical composition comprising an effectiveantiinflammatory amount of a compound of claim 1 which is substantiallyfree of gastrointestinal ulceration in combination with one or morepharmaceutically acceptable carriers.
 11. A pharmaceutical compositioncomprising an effective antiinflammatory amount of a compound of claim 6which is substantially free of gastrointestinal ulceration incombination with one or more pharmaceutically acceptable carriers.
 12. Apharmaceutical composition comprising an effective antiinflammatoryamount of a compound of claim 17 which is substantially free ofgastrointestinal ulceration in combination with one or morepharmaceutically acceptable carriers.
 13. A pharmaceutical compositioncomprising an effective antiinflammatory amount of a compound of claim 8which is substantially free of gastrointestinal ulceration incombination with one or more pharmaceutically acceptable carriers.
 14. Apharmaceutical composition comprising an effective antiinflammatoryamount of a compound of claim 9 which is substantially free ofgastrointestinal ulceration in combination with one or morepharmaceutically acceptable carriers.
 15. A method of treatingcyclooxygenase dependent disorders in mammals without causingundesirable gastrointestinal side effects which comprises administeringto a mammal in need thereof an effective amount of a compound accordingto claim 1 which is substantially free of gastrointestinal ulceration.16. A method of treating rheumatoid arthritis, osteoarthritis, pain orinflammation in mammals without causing undesirable gastrointestinalside effects which comprises administering to a mammal in need thereof acorrespondingly effective amount of a compound of claim 1 which issubstantially free of gastrointestinal ulceration.
 17. A method ofselectively inhibiting cyclooxygenase-2 activity in a mammal withoutsubstantially inhibiting cycloxygenase-1 activity which comprisesadministering to a mammal in need thereof an effective cyclooxygenase-2inhibiting amount, which amount is substantially free ofcyclooxygenase-1 inhibiting activity, of a compound of formula I

wherein R is methyl or ethyl; R₁ is chloro or fluoro; R₂ is hydrogen orfluoro; R₃ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy orethoxy; R₄ is hydrogen or fluoro; R₅ is chloro, fluoro ortrifluoromethyl; or a pharmaceutically acceptable salt thereof; or apharmaceutically acceptable prodrug ester thereof.
 18. A methodaccording to claim 17 wherein the compound is a compound of formula Iwherein R is methyl or ethyl; R₁ is chloro or fluoro; R₂ is hydrogen; R₃is hydrogen, fluoro, chloro or methyl; R₄, is hydrogen; and R₅ is chloroor fluoro; or a pharmaceutically acceptable salt thereof; or apharmaceutically acceptable prodrug ester thereof.
 19. A methodaccording to claim 17 wherein the compound is a compound of formula Iwherein R is methyl or ethyl; R₁ is fluoro; R₂ is hydrogen; R₃ ishydrogen or fluoro; R₄ is hydrogen; and R₅ is chloro; or apharmaceutically acceptable salt thereof; or a pharmaceuticallyacceptable prodrug ester thereof.
 20. A method according to claim 17wherein the compound is a compound of formula I wherein R is methyl orethyl; R₁ is fluoro; R₂ is fluoro; R₃ is hydrogen or ethoxy; R4 isfluoro; and R₅ is fluoro; or a pharmaceutically acceptable salt thereof;or a pharmaceutically acceptable prodrug ester thereof.
 21. A methodaccording to claim 17 wherein the compound is a compound of formula Iwherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is hydrogen orfluoro; R4 is hydrogen; and R₅ is chloro; or a pharmaceuticallyacceptable salt thereof; or a pharmaceutically acceptable prodrug esterthereof.
 22. A method according to claim 17 wherein the compound is acompound of formula I wherein R is methyl or ethyl; R₁ is fluoro; R₂-R₄are hydrogen or fluoro; and R₅ is chloro or fluoro; or apharmaceutically acceptable salt thereof; or a pharmaceuticallyacceptable prodrug ester thereof.
 23. A method according to claim 17wherein the compound is5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid of formula Iwherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is hydrogen; R4 ishydrogen; and R₅ is chloro; or a pharmaceutically acceptable saltthereof.
 24. A method according to claim 17 wherein the compound is5-methyl-2-(2′,4′-difluoro-6′-chloroanilino)phenylacetic acid of formulaI wherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is fluoro; R₄ ishydrogen; and R₅ is chloro; or a pharmaceutically acceptable saltthereof.
 25. A method according to claim 17 wherein the compound is5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid of formula Iwherein R is ethyl; R₁ is fluoro; R₂ is fluoro; R₃ is hydrogen; R₄ isfluoro; and R₅ is fluoro; or a pharmaceutically acceptable salt thereof.26. A method according to claim 23 wherein the compound is5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid.
 27. Aselective cyclooxygenase-2 inhibiting pharmaceutical compositionsubstantially free of cyclooxygenase-1 inhibiting activity comprising aneffective cyclooxygenase-2 inhibiting amount, which amount issubstantially free of cyclooxygenase-1 inhibiting activity, of acompound of formula I

wherein R is methyl or ethyl; R₁ is chloro or fluoro; R₂ is hydrogen orfluoro; R₃ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy orethoxy; R₄ is hydrogen or fluoro; R₅ is chloro, fluoro ortrifluoromethyl; or a pharmaceutically acceptable salt thereof; or apharmaceutically acceptable prodrug ester thereof; in combination withone or more pharmaceutically acceptable carriers.
 28. A selectivecyclooxygenase-2 inhibiting pharmaceutical composition according toclaim 27 comprising an effective cyclooxygenase-2 inhibiting amount,which amount is substantially free of cyclooxygenase-1 activity, of acompound of formula I wherein R is methyl or ethyl; R₁ is chloro orfluoro; R₂ is hydrogen; R₃ is hydrogen, fluoro; chloro or methyl; R₄ ishydrogen; and R₅ is chloro or fluoro; or a pharmaceutically acceptablesalt thereof; or a pharmaceutically acceptable prodrug ester thereof; incombination with one or more pharmaceutically acceptable carriers.
 29. Aselective cyclooxygenase-2 inhibiting pharmaceutical compositionaccording to claim 27 comprising an effective cyclooxygenase-2inhibiting amount which amount is substantially free of cyclooxygenase-1inhibiting activity, of a compound of formula I wherein R is methyl orethyl; R₁ is fluoro; R₂ is hydrogen; R₃ is hydrogen or fluoro; R₄ ishydrogen; and R₅ is chloro; or a pharmaceutically acceptable saltthereof; or a pharmaceutically acceptable prodrug ester thereof; incombination with one or more pharmaceutically acceptable carriers.
 30. Aselective cyclooxygenase-2 inhibiting pharmaceutical compositionaccording to claim 27 comprising an effective cyclooxygenase-2inhibiting amount, which amount is substantially free ofcyclooxygenase-1 inhibiting activity, of a compound of formula I whereinR is methyl or ethyl; R₁ is fluoro; R₂ is fluoro; R₃ is hydrogen orethoxy; R₄ is fluoro; and R₅ is fluoro; or a pharmaceutically acceptablesalt thereof; or a pharmaceutically acceptable prodrug ester thereof; incombination with one or more pharmaceutically acceptable carriers.
 31. Aselective cyclooxygenase-2 inhibiting pharmaceutical compositionaccording to claim 27 comprising an effective cyclooxygenase-2inhibiting amount which amount is substantially free of cyclooxygenase-1inhibiting activity, of a compound of formula I wherein R is methyl; R₁is fluoro; R₂ is hydrogen; R₃is hydrogen or fluoro; R₄ is hydrogen; andR₅ is chloro; or a pharmaceutically acceptable salt thereof; or apharmaceutically acceptable prodrug ester thereof; in combination withone or more pharmaceutically acceptable carriers.
 32. A selectivecyclooxygenase-2 inhibiting pharmaceutical composition according toclaim 27 comprising an effective cyclooxygenase-2 inhibiting amountwhich amount is substantially free of cyclooxygenase-1 inhibitingactivity, of a compound of formula I wherein R is methyl or ethyl; R₁ isfluoro; R₂-R₄ are hydrogen or fluoro; and R₅ is chloro or fluoro; or apharmaceutically acceptable salt thereof; or a pharmaceuticallyacceptable prodrug ester thereof; in combination with one or morepharmaceutically acceptable carriers.
 33. A selective cyclooxygenase-2inhibiting pharmaceutical composition according to claim 27 comprisingan effective cyclodxygenase-2 inhibiting amount which amount issubstantially free of cyclooxygenase-1 inhibiting activity, of5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid of formula Iwherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃is hydrogen; R₄ ishydrogen; and R₅ is chloro; or a pharmaceutically acceptable saltthereof; in combination with one or more pharmaceutically acceptablecarriers.
 34. A selective cyclooxygenase-2 inhibiting pharmaceuticalcomposition according to claim 27 comprising an effectivecyclooxygenase-2 inhibiting amount, which amount is substantially freeof cyclooxygenase-1 inhibiting activity, of5-methyl-2-(2′,4′-difluoro-6′-chloroanilino)phenylacetic acid of formulaI wherein R is methyl; R₁ is fluoro; R₂ is hydrogen; R₃ is fluoro; R₄ ishydrogen; and R₅ is chloro; or a pharmaceutically acceptable saltthereof; in combination with one or more pharmaceutically acceptablecarriers.
 35. A selective cyclooxygenase-2 inhibiting pharmaceuticalcomposition according to claim 27 comprising an effectivecyclooxygenase-2 inhibiting amount, which amount is substantially freeof cyclooxygenase-1 inhibiting activity, of5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid formula Iwherein R is ethyl; R₁ is fluoro; R₂ is fluoro; R₃ is hydrogen; R₄ isfluoro; and R₅ is fluoro; or a pharmaceutically acceptable salt thereof;in combination with one or more pharmaceutically acceptable carriers.36. A selective cyclooxygenase-2 inhibiting pharmaceutical compositionaccording to claim 33 comprising an effective cyclooxygenase-2inhibiting amount, which amount is substantially free ofcycloxxygenase-1 inhibiting activity, of5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid; in combinationwith one or more pharmaceutically acceptable carriers.